In the last decade, psychologists have begun to focus their attention on how to cultivate a better life and on the benefits of positive mood. These efforts have been often limited by a lack of understanding of how the human brain works. Our cognitive neuroscience approach has led to a novel hypothesis, connecting mood and depression with cognitive processing and brain structure and function. Specifically, we propose that mood can be improved significantly when mental processes are made more associative. This relation stems from our inherent need to predict and explore many alternatives in parallel. The hypothesis presented here represents a multidisciplinary synthesis, integrating remote findings. For example, that the same medial prefrontal region that is most indicative of depression treatment success is intensely activated by our cognitive tasks engaging associative and contextual predictions; or the link between the central role of the hippocampus in associative processing and recent indications that the effectiveness of depression therapy is dependent upon the growth of new hippocampal neurons. This framework has many implications, most notably for diagnosing and treating emotional disorders such as depression, for better understanding a host of mood disorders such as, attention-deficit, bi-polar and post traumatic stress disorders, for contextualizing adult hippocampal neurogenesis, and more generally, for increasing well-being and longevity by improving mood. Among mood disorders, major depressive disorder is a leading cause of disability, affecting annually more than 15 million people, with an estimated economic impact exceeding $50 billion in the United States alone. Although restoring the neurochemical balance has been the primary strategy for treating depression, many patients do not achieve adequate response. The adverse characteristics of depression contribute to long-term structural and functional neurobiological alterations that in turn, are known to further increase the probability and the number of future depressive episodes. We propose a novel perspective to essentially reverse this spiraling progression of the disorder without any adverse side effects using a cognitive neuroscience framework. We adopt a multimodal imaging approach, capitalizing on the complementary strengths of psychophysical paradigms, fMRI and magnetoencephalography, to achieve the following specific aims: In Aim 1 we will test all relevant aspects of the relationship between associative predictions and mood, in healthy adults and in clinical populations. This will include the relation between associative processing and: brain structure, brain activation, subjective performance, nature of individual thought patterns, and mood measures. In Aim 2 we plan to investigate the neural mechanism connecting mood with associative processing, focusing on morphological characteristics, network dynamics and functional interactions. Finally, in Aim 3 we plan to use our accumulated knowledge to start developing a non-intrusive approach, free of side-effects, to train and rebuild the underlying cortical circuitry such that thought pattern is modified from its core to better serve mood-related well-being. PUBLIC HEALTH RELEVANCE: In this proposal we hypothesize a direct link between depression and associative cognitive processing. Finding that reduced cognitive associative processing has a causal role in mood disorders would have profound implications for theories of major depression and other affective disorders. Translating these findings to the design of novel cognitive tasks that can enhance associative processing and help to alleviate the effects of depression has the potential to positively impact millions of individuals suffering from mood disorders.